Some of the most prominent and characteristic symptoms of recurrent affective illnesses, e.g., bipolar and unipolar disorders, include dramatic disturbances in the sleep:wake or rest:activity cycle. It has been shown that manipulations of rest:activity cycles can profoundly change the course of clinical manifestations of these illnesses. These findings suggest that genetic predisposition to alterations in sleep:wake or rest:activity cycles represent endophenotypes for recurrent affective disorders. Based on recent findings that gene expression of 5-10% of genes in the genome are controlled by the clock (Akhtar et al., 2002; Panda et al., 2002), we propose that clock genes and/or genes that are controlled by the clock may underlie polygenic inheritance of the bipolar disorder. Recent findings that cultured skin fibroblasts, following a serum shock (50% fetal bovine serum) exhibit synchronized cycling in the expression of core clock genes (Balsalobre et al., 1998; Nagoshi et al., 2004) provide a new avenue to investigate the link between bipolar illness and the circadian system. The purpose of this application is to explore the possibility of using fibroblasts derived from skin biopsies of bipolar patients to investigate their intrinsic circadian clock. Specifically, our aims are: Aim 1. To develop a high-throughput method for monitoring circadian rhythms in human cultured fibroblasts to examine cycling expression of core clock and clock-controlled genes by Real-time quantitative PCR and bioluminescence recording; and Aim 2. To apply the method to examine if the core clock machinery is involved in the pathophysiology of bipolar disorder. In this aim will involve analysis of fibroblasts cell-lines available through the Coriell Cell Repositories (Important note: The identity of the specific individuals that were the source of the original cells is not known to the repository).This highly exploratory project has a tremendous potential for accelerating our understanding of the genetic basis of an important mental disorder. [unreadable] [unreadable] [unreadable]